The immune system of mammals, and specifically humans, is a finely balanced interaction between cellular responses and molecular responses. Cellular responses include reactions initiated by phagocytes, monocytes, and cytotoxic T cells. Molecular responses include the production of immunoglobulins, antibodies, initiation of complement, etc. It is the responsibility of the immune system in this coordinated effort to form a barrier between self and non-self and to protect us against invasion of external potentially harmful substances. Nonetheless, animals routinely consume a multitude of foreign material in the form of nutrients and inhale numerous foreign airborne particles. Reproduction of mammalian life itself depends on a female being impregnated with an egg fertilized by sperm, in essence a foreign body to the female, and carrying a child internally for nine months only partially like herself. In the vast majority of individuals, these daily exposures to foreign matter elicit little, if any, noticeable immune activity. Much of our understanding of the function of each part of the immune system has come from the study of individuals who lack some particular component or who are deficient in a specific activity. While some imbalances within this complex coordinated endeavor can be compensated for and tolerated by the host, others lead to unhealthy, dangerous conditions.
The subdivision of the immune system which seems to be the most well poised to maintain this equilibrium is located just below the mucosal epithelium throughout the body and is collectively known as the mucosal immune network. The mucosal immune network accounts for over 85 percent of all lymphoid tissue and specializes not only in acting as a deterrent to keep foreign matter from entering the body but also prevents over-stimulation of the systemic immune system. Excessive stimulation of the systemic immune system often results in bystander tissue damage and destruction.
The major immunoglobulin produced by the mucosal immune network is immunoglobulin A (IgA) which is secreted by activated, differentiated lymphocytes in the lamina propria. The structure and function of IgA is quite distinct from that of systemically produced immunoglobulin G (IgG). These differences in structure and function of IgA are in accordance with the major objectives of mucosal immunity. Firstly, IgA molecules occur predominantly as dimers and tetramers and have four to eight antigen-binding sites. This increase in binding-site density is one explanation for the greater avidity of IgA for foreign antigens as compared to that of IgG. Secondly, increased glycosylation of IgA molecules helps to protect them from proteolytic digestive enzymes found in the gut. Thirdly, IgA molecules also contain regions important for their active displacement from the lamina propria to the outside of the body. This active transport mechanism seems to perform two important functions. It maintains the largest amount of IgA at the site of highest exposure to foreign substances, for example, on the surfaces of the gastrointestinal, pulmonary, and urogenital tracts. It has been shown that IgA present on these surfaces inhibit binding and subsequent penetration of pathogens and allergens across the epithelial cell boundary. If by chance some foreign material does breach the epithelium, the second important function of the active transport mechanism is to bind the antigen either within epithelial cells or in the lamina propria and to remove it from the body via excremental pathways.
Another important function of IgA is to keep the responsiveness of the immune system to a minimum. However, the ability of the immune system to intensify at times is clearly important. This happens, for example, when physical injury occurs or when an accumulation of pathogens overwhelms the mucosal immunity. Yet obviously this intense activity cannot and should not occur every time an animal consumes food. Nor should such intensity, once initiated, remain sustained over long periods of time. However, once the immune system is activated, IgA down-regulates this activity as soon as possible in order to regain the proper and healthy equilibrium in the immune system. IgA molecules accomplish this task by intervention into the complement cascade.
In conjunction with systemic immunity and IgG, the complement system is a group of proteins which, through a progression of reactions, amplify and intensify immunological responses. It has been shown that IgG molecules aligned in close proximity initiate the reaction. This can occur, for example, when IgG molecules attach to bacteria or other foreign bodies. The end product of this reaction, called the membrane act complex or MAC, inserts itself into the invading organism causing cell lysis and death.
When levels of IgA are diminished or completely lacking, the complement cascade can be initiated. In carefully controlled studies, it has been demonstrated that by the addition and subsequent interdigitation of a relatively few IgA molecules between molecules of IgG, the complement cascade can be inactivated (Russell-Jones et al. 1980). This in turn down-regulates all subsequent immune activation events. In addition, the ability of IgA to minimize cellular immune responses is less well documented but nonetheless evident (Russell-Jones et al. 1981).
Examples of what results when the mucosal immune system becomes imbalanced have been reported. The simplest, most easily identified irregularity of the mucosal immune system is the complete absence, or reduced production, of IgA. The frequency of this condition has been reported as high as 1 out of every 400 individuals (Eckrich et al. 1993; Sandler et al. 1995). Patients exhibiting diminished or non-existent levels of IgA reveal themselves by having an inordinate number of allergies and allergic reactions. Such individuals are also frequently identified with severe serum reactions following blood transfusions and gamma globulin therapy (Sandler et al. 1995; Misbah & Chapel, 1993; Dabrow & Wilkins, 1993).
At the other end of the spectrum, the elevation of IgA has been, until recently, less frequently observed. Indeed, scientists interested in exploiting the mucosal immune system for vaccine purposes have been frustrated by the inability to mount and sustain a significant, specific IgA response. Most often, IgA has been studied in isolation and out of context with the other components of the immune system. These studies have shown that IgA can bind to and inhibit the interactions of pathogens within human cells and tissue. Ways to increase IgA activity against pathogens has been a major avenue of research.
Although the ratio of IgA to IgG for a specific antigen usually remains within a relatively narrow range, variations in this ratio have been reported. A recent study demonstrated that patients with increased levels of IgA reactive to their foreign, transplanted kidneys had significantly lower rates of rejection compared with patients with lower IgA levels (Lim et al. 1993). The investigators proposed that anti-HLA IgA antibody contributed to the high kidney graft survival in patients with elevated IgA by blocking IgG antibodies or inhibiting cellular immune responses. This study suggested that elevated levels of IgA may have an impact on cellular responses of the immune system and graft rejection.
The effects of abnormally elevated IgA/IgG ratios have also been described by researchers studying an outbreak of bacterial meningitis in Seattle, Wash. (Griffiss & Bertram, 1977; Griffiss, 1975; Griffiss, 1983; Griffiss & Goroff, 1983; Griffiss, 1982). These studies showed that the majority of patients in this outbreak had elevated levels of IgA reactive to the invading meningococcal pathogens compared to uninfected controls and that sera from these patients were unable to kill the bacteria. However, after the IgA was removed from the patients' sera, the serum was then able to destroy the bacteria. It was felt that these patients were originally normally immune and had the ability to destroy as well as resist infection by these pathogens, but, due to an immune response of unknown origin, the IgA/IgG ratio became imbalanced and the increased anti-meningococcal IgA may have interfered with the ability of systemic IgG and complement to eliminate these organisms. Similar effects have been observed for other pathogenic bacteria (Apicella et al. 1986; Musher et al. 1984; Taylor, 1972). Elevation in specific IgA antibodies reactive to tumor antigens has been observed in women with malignant ovarian carcinomas as compared with normal women or women with benign tumors (Gupta et al. 1994). In addition, a statistically significant correlation has been found with increased levels of IgA antibody reactive to the Epstein-Barr virus and the appearance of esophageal cancer in patients from Southeast Asia (Filipovich et al. 1994).
All of the reports referred to above have focused on elevations in the levels of IgA immunoreactive to a specific antigen. Thus, in most cases, the concentration of IgA antibody to a specific antigen was increased, but the overall total concentration of IgA was not increased. An association between elevated levels of IgA has been observed in nephropathy and kidney disease (Lim et al. 1993), but the genesis of this IgA is unknown. Recently, it has been demonstrated that HIV seropositive individuals have a statistically significant increase in IgA as they progress into AIDS, whereas serum levels of other immunoglobulins remain normal (Quesnel et al. 1994a; Quesnel et al. 1994b; Anonymous, 1994). The concentration of IgA continued to rise in these patients and upon their death was several hundred-fold above normal levels. How this elevation in IgA affects all of the symptoms and diseases which afflict AIDS patients is unknown. It has been shown in isolated instances that vaccination to increase systemic IgG levels improves the specific immunity for which the vaccine was made (Conlon, 1993; Birx et al. 1991; Rhoads et al. 1991; Guerra et al. 1992). However, it is impossible to raise systemic IgG antibody levels to each of the antigens to which the IgA levels have become elevated.
The ability to accomplish extracorporeal removal of certain components from bodily fluids without increased risks to the patient has been established. Although extracorporeal devices, such as kidney dialysis machines, are known in the art and have been shown to be therapeutically effective in eliminating abnormally high concentrations of certain components of serum, none of these extracorporeal devices are directed to specifically removing IgA from blood or serum. Moreover, there is no teaching or suggestion in the art directed to the extracorporeal removal or reduction of IgA from biological fluids as a therapeutic treatment for immunocompromised patients, particularly those patients that are infected with HIV. U.S. Pat. No. 4,801,449 which issued to Balint, Jr. et al. discloses an immunoadsorbent material comprising Protein A for removing IgG from biological fluids as a method for treating Kaposi's sarcoma. U.S. Pat. No. 5,122,112, which issued to Jones teaches a method for treating antigen-related disease by identifying the predominant antigen associated with the disease and then using an antigen-specific immunoadsorbent to remove the antigen from a patient's system.